BioPAX pathway converted from "Insulin processing" in the Reactome database. Insulin processing This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Oxidation of cysteine to cystine in Proinsulin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> INS INS(25-110) P67970 Reactome DB_ID: 10545690 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 UniProt:P67970 INS Gallus gallus NCBI Taxonomy 9031 UniProt P67970 25 EQUAL 110 EQUAL Reactome Database ID Release 81 10545690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545690 Reactome R-GGA-264893 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264893.1 Reactome http://www.reactome.org INS 6xHC-INS(25-110) P67970 Reactome DB_ID: 10545692 31 EQUAL L-cystine (cross-link) MOD MOD:00034 43 EQUAL 95 EQUAL 25 EQUAL 110 EQUAL Reactome Database ID Release 81 10545692 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545692 Reactome R-GGA-265075 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265075.1 ACTIVATION Converted from EntitySet in Reactome EROIL-like Proteins Reactome DB_ID: 10545702 ERO1A ERO1L E1C0W7 Reactome DB_ID: 10545696 UniProt:E1C0W7 ERO1A UniProt E1C0W7 24 EQUAL 468 EQUAL Reactome Database ID Release 81 10545696 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545696 Reactome R-GGA-265076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265076.1 ERO1B ERO1LB A0A1D5P5D8 Reactome DB_ID: 10545700 UniProt:A0A1D5P5D8 ERO1B UniProt A0A1D5P5D8 34 EQUAL 467 EQUAL Reactome Database ID Release 81 10545700 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545700 Reactome R-GGA-4084704 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-4084704.1 Reactome Database ID Release 81 10545702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545702 Reactome R-GGA-4084703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-4084703.1 GENE ONTOLOGY GO:0015036 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 10545703 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545703 Reactome Database ID Release 81 10545705 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545705 Reactome R-GGA-264997 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264997.1 Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteine residues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directly catalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizing environment for the reactions to occur . Though Ero1-like alpha can act via specific isomerases such as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulin requires a specific isomerase. Interestingly, even in beta cells of wild type animals, trace amounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystine bonds may involve a period of bond shuffling. 14744022 Pubmed 2003 Role of disulfide bonds in the structure and activity of human insulin Chang, SG Choi, KD Jang, SH Shin, HC Mol Cells 16:323-30 12590147 Pubmed 2003 Role of the connecting peptide in insulin biosynthesis Liu, M Ramos-Castañeda, J Arvan, P J Biol Chem 278:14798-805 12624089 Pubmed 2003 In vitro refolding of human proinsulin. Kinetic intermediates, putative disulfide-forming pathway folding initiation site, and potential role of C-peptide in folding process Qiao, ZS Min, CY Hua, QX Weiss, MA Feng, YM J Biol Chem 278:17800-9 15096212 Pubmed 2004 Unfolding of human proinsulin. Intermediates and possible role of its C-peptide in folding/unfolding Min, CY Qiao, ZS Feng, YM Eur J Biochem 271:1737-47 9631292 Pubmed 1998 The role of assembly in insulin's biosynthesis Dodson, G Steiner, D Curr Opin Struct Biol 8:189-94 15705595 Pubmed 2005 Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum Liu, M Li, Yun Cavener, D Arvan, P J Biol Chem 280:13209-12 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT Cystine-bonded Proinsulin translocates from the endoplasmic reticulum to the Golgi This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> INS 6xHC-INS(25-110) P67970 Reactome DB_ID: 10545684 Golgi lumen GENE ONTOLOGY GO:0005796 25 EQUAL 110 EQUAL Reactome Database ID Release 81 10545684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545684 Reactome R-GGA-264890 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264890.1 Reactome Database ID Release 81 10545707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545707 Reactome R-GGA-265010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265010.1 Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud from the endoplasmic reticulum. 3896518 Pubmed 1985 Direct identification of prohormone conversion site in insulin-secreting cells Orci, L Ravazzola, M Amherdt, M Madsen, O Vassalli, JD Perrelet, A Cell 42:671-81 LEFT-TO-RIGHT ZnT6 transports zinc into the golgi apparatus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 29426 cytosol GENE ONTOLOGY GO:0005829 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 29426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29426 Reactome R-ALL-29426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29426.3 COMPOUND C00038 additional information MI MI:0361 Zn2+ Zinc 2+ zinc(2+) Reactome DB_ID: 216667 Reactome Database ID Release 81 216667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=216667 Reactome R-ALL-216667 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-216667.3 ACTIVATION SLC30A6 SLC30A6 A0A452J7U2 Reactome DB_ID: 10553701 Golgi membrane GENE ONTOLOGY GO:0000139 UniProt:A0A452J7U2 SLC30A6 UniProt A0A452J7U2 1 EQUAL 461 EQUAL Reactome Database ID Release 81 10553701 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553701 Reactome R-GGA-437099 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437099.1 GENE ONTOLOGY GO:0005385 Reactome Database ID Release 81 10553702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553702 Reactome Database ID Release 81 10553704 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553704 Reactome R-GGA-437139 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437139.1 Two human genes mediate the transport of zinc into the TGN and they are both localized to the TGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies, ZnT6 is only found in the brain and lung in human (Huang L et al, 2002). 11997387 Pubmed 2002 Functional characterization of a novel mammalian zinc transporter, ZnT6 Huang, L Kirschke, CP Gitschier, J J Biol Chem 277:26389-95 LEFT-TO-RIGHT Proinsulin binds zinc and calcium forming Proinsulin:zinc:calcium This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 6 Ca2+ Calcium calcium(2+) Reactome DB_ID: 167012 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 81 167012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167012 Reactome R-ALL-167012 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-167012.3 COMPOUND C00076 6xProinsulin:2xZn2+:1xCa2+ Reactome DB_ID: 10545686 2 6 1 Reactome Database ID Release 81 10545686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545686 Reactome R-GGA-264908 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264908.1 Reactome Database ID Release 81 10545688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545688 Reactome R-GGA-264976 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264976.1 In the presence of high concentrations of zinc and calcium, proinsulin spontaneously forms soluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. Zinc Transporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells (and also in many other cell types). They play a role in maintaining the high zinc concentration in the Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Other transporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this is presently unknown. 16158220 Pubmed 2005 Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a review Dunn, MF Biometals 18:295-303 2669954 Pubmed 1989 Comparison of solution structural flexibility and zinc binding domains for insulin, proinsulin, and miniproinsulin Kaarsholm, NC Ko, HC Dunn, MF Biochemistry 28:4427-35 10521251 Pubmed 1999 Role of metal ions in the T- to R-allosteric transition in the insulin hexamer Kadima, W Biochemistry 38:13443-52 14704853 Pubmed 2004 Overview of mammalian zinc transporters Kambe, T Yamaguchi-Iwai, Y Sasaki, R Nagao, M Cell Mol Life Sci 61:49-68 LEFT-TO-RIGHT Proinsulin:Zinc:Calcium complex translocates to immature secretory granule This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 6xProinsulin:2xZn2+:1xCa2+ Reactome DB_ID: 10545711 secretory granule lumen GENE ONTOLOGY GO:0034774 Ca2+ Calcium calcium(2+) Reactome DB_ID: 216801 Reactome Database ID Release 81 216801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=216801 Reactome R-ALL-216801 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-216801.3 1 Zn2+ Zinc 2+ zinc(2+) Reactome DB_ID: 216785 Reactome Database ID Release 81 216785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=216785 Reactome R-ALL-216785 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-216785.3 2 INS 6xHC-INS(25-110) P67970 Reactome DB_ID: 10545709 25 EQUAL 110 EQUAL Reactome Database ID Release 81 10545709 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545709 Reactome R-GGA-264984 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264984.1 6 Reactome Database ID Release 81 10545711 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545711 Reactome R-GGA-265073 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265073.1 Reactome Database ID Release 81 10545713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545713 Reactome R-GGA-265153 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265153.1 Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from the trans-golgi network. LEFT-TO-RIGHT ZnT5 transports zinc into secretory granules in pancreatic beta cells This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION Q5ZLF4 SLC30A5 SLC30A5 Reactome DB_ID: 10553687 secretory granule membrane GENE ONTOLOGY GO:0030667 UniProt:Q5ZLF4 SLC30A5 UniProt Q5ZLF4 1 EQUAL 765 EQUAL Reactome Database ID Release 81 10553687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553687 Reactome R-GGA-437105 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437105.1 Reactome Database ID Release 81 10553688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553688 Reactome Database ID Release 81 10553690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553690 Reactome R-GGA-437085 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437085.1 The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressed but is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5 mediates the transport of zinc into secretory granules that contain insulin. 11904301 Pubmed 2002 Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic beta cells Kambe, T Narita, H Yamaguchi-Iwai, Y Hirose, J Amano, T Sugiura, N Sasaki, R Mori, K Iwanaga, T Nagao, M J Biol Chem 277:19049-55 LEFT-TO-RIGHT SLC30A8 transports Zn2+ from cytosol to secretory granule ZnT8 transports zinc into the secretory vesicles of pancreatic beta cells specifically This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION SLC30A8 SLC30A8 A0A1D5NY81 Reactome DB_ID: 10553694 UniProt:A0A1D5NY81 SLC30A8 UniProt A0A1D5NY81 1 EQUAL 369 EQUAL Reactome Database ID Release 81 10553694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553694 Reactome R-GGA-437106 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437106.1 Reactome Database ID Release 81 10553695 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553695 Reactome Database ID Release 81 10553697 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10553697 Reactome R-GGA-437136 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-437136.1 The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed in pancreatic beta cells (Chimienti et al. 2005). Zinc is required for zinc-insulin crystallization within secretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secreted locally in the extracellular matrix together with insulin. It has been suggested that this co-secreted zinc plays a role in islet cell paracrine and/or autocrine communication (Chimienti F et al, 2006). Loss of function mutations in SLC30A8 are strongly protective against type 2 diabetes, suggesting SLC20A8 inhibition as a therapeutic target in T2D prevention. (Flannick et al. 2014). 16984975 Pubmed 2006 In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion Chimienti, F Devergnas, S Pattou, F Schuit, F Garcia-Cuenca, R Vandewalle, B Kerr-Conte, J Van Lommel, L Grunwald, D Favier, A Seve, M J Cell Sci 119:4199-206 16158222 Pubmed 2005 ZnT-8, a pancreatic beta-cell-specific zinc transporter Chimienti, Fabrice Favier, Alain Seve, Michel Biometals 18:313-7 LEFT-TO-RIGHT Exocyst complex formation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EXOC8 EXOC8 A0A1D5P0R2 Reactome DB_ID: 10545733 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:A0A1D5P0R2 EXOC8 UniProt A0A1D5P0R2 1 EQUAL 725 EQUAL Reactome Database ID Release 81 10545733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545733 Reactome R-GGA-264948 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264948.1 EXOC5 EXOC5 F1NF87 Reactome DB_ID: 10545725 UniProt:F1NF87 EXOC5 UniProt F1NF87 1 EQUAL 708 EQUAL Reactome Database ID Release 81 10545725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545725 Reactome R-GGA-265045 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265045.1 EXOC3 EXOC3 F1NHD9 Reactome DB_ID: 10545741 UniProt:F1NHD9 EXOC3 UniProt F1NHD9 1 EQUAL 756 EQUAL Reactome Database ID Release 81 10545741 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545741 Reactome R-GGA-2872286 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-2872286.1 EXOC7 EXOC7 A0A1D5PP34 Reactome DB_ID: 10545745 UniProt:A0A1D5PP34 EXOC7 UniProt A0A1D5PP34 1 EQUAL 735 EQUAL Reactome Database ID Release 81 10545745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545745 Reactome R-GGA-2872288 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-2872288.1 EXOC1 EXOC1 A0A1D5P158 Reactome DB_ID: 10545737 UniProt:A0A1D5P158 EXOC1 UniProt A0A1D5P158 2 EQUAL 894 EQUAL Reactome Database ID Release 81 10545737 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545737 Reactome R-GGA-2872284 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-2872284.1 EXOC6 EXOC6 A0A1D5P7W7 Reactome DB_ID: 10545729 UniProt:A0A1D5P7W7 EXOC6 UniProt A0A1D5P7W7 1 EQUAL 804 EQUAL Reactome Database ID Release 81 10545729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545729 Reactome R-GGA-265041 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265041.1 EXOC4 EXOC4 A0A3Q2UC94 Reactome DB_ID: 10545717 UniProt:A0A3Q2UC94 EXOC4 UniProt A0A3Q2UC94 2 EQUAL 974 EQUAL Reactome Database ID Release 81 10545717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545717 Reactome R-GGA-264989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264989.1 EXOC2 EXOC2 F1P2A7 Reactome DB_ID: 10545721 UniProt:F1P2A7 EXOC2 UniProt F1P2A7 1 EQUAL 924 EQUAL Reactome Database ID Release 81 10545721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545721 Reactome R-GGA-264887 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264887.1 Exocyst Complex Reactome DB_ID: 10545747 1 1 1 1 1 1 1 1 Reactome Database ID Release 81 10545747 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545747 Reactome R-GGA-264974 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264974.1 Reactome Database ID Release 81 10545749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10545749 Reactome R-GGA-265177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-265177.1 A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). As inferred from rat MIN6 cells, docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane (Matern et al. 2001). 16714477 Pubmed 2006 Insulin vesicle release: walk, kiss, pause ... then run Rutter, GA Hill, EV Physiology (Bethesda) 21:189-96 15878854 Pubmed 2005 Mammalian exocyst complex is required for the docking step of insulin vesicle exocytosis Tsuboi, T Ravier, MA Xie, H Ewart, MA Gould, GW Baldwin, SA Rutter, GA J Biol Chem 280:25565-70 11493706 Pubmed 2001 The Sec6/8 complex in mammalian cells: characterization of mammalian Sec3, subunit interactions, and expression of subunits in polarized cells Matern, HT Yeaman, C Nelson, WJ Scheller, RH Proc Natl Acad Sci U S A 98:9648-53 Reactome Database ID Release 81 10616361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10616361 Reactome R-GGA-264876 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-264876.1 GENE ONTOLOGY GO:0030070 gene ontology term for cellular process MI MI:0359 The generation of insulin-containing secretory granules from proinsulin in the lumen of the endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane.<br>Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.<br>The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.<br>In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha<br>The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin forms complexes with zinc and calcium.<br>Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secreted with the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule<br>The insulin-containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin-1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.<br>A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is a calcium-dependent process due to interaction of the calcium-binding membrane protein Synaptotagmin V/IX with the SNARE-type proteins. 11815463 Pubmed 2002 Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion Bratanova-Tochkova, TK Cheng, H Daniel, S Gunawardana, S Liu, YJ Mulvaney-Musa, J Schermerhorn, T Straub, SG Yajima, H Sharp, GW Diabetes 51:S83-90 11815450 Pubmed 2002 Molecular determinants of regulated exocytosis Gerber, SH Südhof, TC Diabetes 51:S3-11 16549443 Pubmed 2006 Regulation of the insulin gene by glucose and fatty acids Poitout, V Hagman, D Stein, R Artner, I Robertson, RP Harmon, JS J Nutr 136:873-6